Abstract
Methylglyoxal (MG) is a reactive metabolite involved in diabetes and aging through the formation of protein adducts. Less is known about the extent that MG and its metabolic product S-d-lactoylglutathione (LGSH) form adducts with cell metabolites. Using a ‘symmetric’ isotope-labeled and reactivity-based metabolomics approach in living cells, we found over 200 adducts and, surprisingly, discovered that 10 of the most abundant are lactoylated amino acids mainly derived from LGSH. The most abundant adduct d-Lac-Cys is formed rapidly between LGSH and cysteine, whereas the diastereoisomer l-Lac-Cys is formed directly from MG and cysteine, assigning cysteine with both glyoxalase 1-like and glyoxalase 2-like activity. Cellular cysteine and MG dynamically regulate d-Lac-Cys and l-Lac-Cys levels and the adducts are increased in diabetes, suggesting their use as novel biomarkers. Lastly, cysteine amides, as proxies for protein cysteines, also undergo lactoylation by MG and LGSH, suggesting the existence of two additional pathways for nonenzymatic lactoylation of proteins.
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Data availability
The metabolomics datasets generated during the current study were deposited to the MetaboLight repository with dataset identifier MTBLS6287. All other datasets generated and analyzed during the current study are presented in the manuscript or Supplementary Information. Source data are provided with this paper.
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Acknowledgements
This work was generously supported by Ingeborg og Leo Dannins Legat (J.nr. 10017-1, to M.J.), the Novo Nordisk Foundation (NNF20OC0065548, to M.J.), the Graduate School of Health, Aarhus University (to M.D.O.) and the Danish Diabetes Academy (PhD001-19, to S.B.O.). This project received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program (grant agreement 865738, to T.B.P.). Financial support was provided by National Institutes of Health grants: R35 GM137910 and R01 DK133196 to J.J.G.
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M.J. conceptualized and, together with J.H., supervised the study. M.D.O. and M.B.S. performed the reactivity-based metabolomics experiments. C.B.N. performed preprocessing of the metabolomics data and T.W. assisted in the identification of isotopic pairs. C.B.N., M.D.O., M.B.S. and L.V.B. performed the feature identification and MS2 fragmentations. J.H. and M.B.S. designed, performed and analyzed the cystine-based cell experiments. J.H. and M.B.S. performed the chemoproteomic experiment and analyzed the data. M.D.O. and L.V.B. performed and analyzed the in vitro experiments with isolated amino acids and LGSH or MG. L.V.B. and J.H. performed the kinetic analysis involving LGSH, AcSCoA, MG and cysteine and D.B. performed the computational analysis of the reaction rate for the GLO1-like reaction. C.B.H. designed and performed the in vivo study with the diabetes mouse model and carried out the creatinine and blood glucose measurements under the supervision of J.A.Ø. M.B.S. and C.B.N. performed the urine sample extraction and MRM-based analysis. M.B.S. and K.F. synthesized the lactoylated amino acids, S.B.O. synthesized the isotopically labeled MG and A.M synthesized the d-Lac-Cys and l-Lac-Cys dimers under the supervision of T.B.P. J.M.S. performed the mouse d-Lac experiment under the supervision of R.R.N. J.J.G. generated the GLO2 KO cell line. K.L.N. conducted the initial analysis to identify the lactoylated amino acids. M.J., in collaboration with M.D.O., J.H. and M.B.S., wrote the manuscript and prepared the figures with contributions from T.B.P. and input from all other authors.
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Extended data
Extended Data Fig. 1 Volcano plot of reactivity-based metabolomics data in positive ionization mode.
Volcano plot comparing the ‘light’ (12C3) and ‘heavy’ (13C3) treatment groups from the experiment depicted in Fig. 2a in ESI+ mode (n = 5)(left). The y-axis represents the log10-transformed p-values calculated by an unpaired t-test. The x-axis shows the log10-transformed feature ratio 12C3-MG sample/13C3-MG sample. MG-pairs were considered significant at a ratio cutoff of <0.8 or >1.2 and a p-value < 0.05 (unpaired t-test; equal, or unequal variance based on an F-test; p-values provided in source data). The numbers indicate matching pairs of identified features. Pie chart showing MG pairs discovered in both ionization modes (yellow), pairs selectively found in positive ionization mode (ESI+; red) and pairs selectively found in negative ionization mode (ESI−;blue)(right).
Extended Data Fig. 2 Glyoxalase 1 like mechanism of formation of D- and L-Lac-Cys from MG and cysteine.
(a) Extracted ion chromatogram (EIC) of D-Lac-Cys, L-Lac-Cys and of in vitro reaction mixture of 50 μM MG and 150 μM cysteine (24h) demonstrating that D-Lac-Cys and L-Lac-Cys are formed directly from MG and cysteine (MG + Cys)(left). MS/MS spectra of peaks corresponding to D-Lac-Cys and L-Lac-Cys in reaction mixture (right). MS/MS spectra can be compared to MS/MS spectra of D-Lac-Cys and L-Lac-Cys in Fig. 2. (b) Methylglyoxal (MG, 1.3%) is in a fast equilibrium with a monohydrate (MG(H2O) 28.8%), dihydrate (MG(H2O)2, 69.9%) and a hemithioacetal (HTA, 0.2%) when mixed with 150 μM cysteine in an aqueous buffer. After mixing, HTA rearranges into initially S,D/L-Lac-Cys by a glyoxalase 1 like rearrangement followed by a S-to-N lactoyl transfer to finally form D- and L-Lac-Cys in a ratio of 1:2 and with a first order rate constant k of 10−3-10−4 s−1. For details of computational calculations see Supplementary Note 1.
Extended Data Fig. 3 Cysteine amides undergo glyoxalase 1 reactions to form hydrolytically instable thioesters.
(a) Methylglyoxal (MG, 80 µM) incubated with glutathione (GSH, 0.15 or 2 mM) in PBS at 37 °C and the non-enzymatic formation of S,D-lactoylglutathione (LGSH) was followed in a 24-hour period. The Glo1 enzyme catalyzed reaction was investigated by quantifying LGSH before and after adding Glo1 (10 µM) to a reaction between MG (80 µM) and GSH (2 mM) in PBS at 37 °C. (b) The stability of LGSH in PBS at 37 °C. (c) Lactate formation from LGSH in the reactions described in (a and b). (d) Lactate formation from MG (2 mM) in PBS or H2O at 37 °C. The effects of adding cysteine (Cys, 0.2 or 2 mM) or N-acetylcysteine (NAC, 0.2 or 2 mM) to MG in PBS was studied in additional reactions. All reactions were performed with three replicates and the mean values +/− SD for all timepoints are shown. LGSH and lactate were quantified by LC-MS/MS as described in the methods and material section.
Extended Data Fig. 4 Preferential formation of D-lactoylated metabolites in GLO2 KO cells.
(a) Immunoblot of GLO2 and GAPDH in WT and GLO2 KO cells. Shown are protein data from 3 independent cultures of each cell type analyzed on the same blot. (b) Volcano plot comparing the ‘light’ (12C3) and ‘heavy’ (13C3) treatment groups from the experiment depicted in Fig. 3 in ESI+ mode (n = 5)(left). The y-axis represents the log10-transformed p-values calculated by an unpaired t-test. The x-axis shows the log10-transformed feature ratio 12C3-MG sample/13C3-MG sample. MG-pairs were considered significant at a ratio cutoff of <0.8 or >1.2 and a p-value <0.05 (unpaired t-test; equal, or unequal variance based on an F-test; p-values provided in source data). Pale colored circles (red and blue) show matching MG-pairs (20) also observed in the WT experiment (see Fig. 2a,b). Darker colored circles (red and blue) indicate additional MG pairs observed in GLO2 KO cells (112). Pie chart showing MG pairs discovered in both ionization modes (yellow), pairs selectively found in positive ionization mode (ESI+; red) and pairs selectively found in negative ionization mode (ESI− ;blue)(right).
Extended Data Fig. 5 LGSH trans-acylates around 200 times faster than AcASCoA with cysteine as acceptor.
(a) Yield of D-Lac-Cys and elimination of LGSH monitored as function of time for the reaction between 1 µM LGSH and 50-250 µM cysteine (Cys) under simulated physiological conditions (top). Yield of D-Lac-Cys and elimination of LGSH from a single data series using 1 µM LGSH and 100 µM cysteine (Cys)(bottom left). Elimination of LGSH at the five different levels of cysteine (bottom middle). Rate of reaction (k = 10 M−1S−1) determined as slope of curve from plot of observed rate constants (k’) at the five different cysteine concentrations (M)(bottom right). All reaction time courses were performed three independent times and mean values ± SD (n = 3) are shown. See method section and source data for further details and calculations. (b) Yield of N-acetyl cysteine (NAC) monitored as function of time for the reaction between 10 µM AcSCoA and 50-250 µM cysteine (Cys) under simulated physiological conditions (top). Yield of NAC as function of time for a single data series using 10 µM AcSCoA and 50–100 µM cysteine (bottom left). Formation of NAC over time at the five levels of cysteine (bottom middle). Rate of reaction (k = 0.05 M−1 S−1) determined as slope of curve from plot of observed rate constants (k’) at the four different cysteine concentrations (M)(bottom right). All reaction time courses were performed three independent times and mean values ± SD (n = 3) are shown. See method section for further experimental details and source data for further calculations.
Extended Data Fig. 6 Cysteine impact on AGEs (MG-H1 and CEA) and Lac-Cys kinetics in cells.
(a) Relative levels of reduced glutathione (GSH) by LC-MS/MS after cystine (Cys2) pre-conditioning (1, 2.5 mM or vehicle for 6h) in WT and GLO2 KO cells. Mean values ± SD (n = 4) are shown. P-values for WT cells (P = 0.2 for 1 mM Cys vs vehicle and P = 0.5 for 2.5 mM vs vehicle), and for GLO2 KO (P = 0.23 and P = 0.56). (b) MG-H1 and (c) CEA levels after exhaustive enzymatic hydrolysis of protein material from cells challenged with MG (0.5 mM for 6 hours) following a 6-hour pre-conditioning period in cystine. P-values for testing MG-H1 levels (b) in cystine vs vehicle (WT: p = 0.7 (1 mM), p = 0.56 (2.5 mM), and for GLO2 KO: p = 0.02 (1 mM), p = 0.09 (2.5 mM). P-values for testing CEA MG-H1 levels (c) in cystine vs vehicle (WT: p = 0.75 (1 mM), p = 0.92 (2.5 mM), and for GLO2 KO: p = 0.22 (1 mM), p = 0.14 (2.5 mM). Data shown in (b-c) are means ± SD from 5 cell cultures (n = 5). Test of means (a-c) based on a one-way ANOVA using a Dunnet´s post-hoc test; ns p > 0.05, *p < 0.05. (d) and (e) Kinetics of formation (24-hour period) of stable isotope labelled D-Lac-Cys (d) and L-Lac-Cys (e) after a pulse of 0.5 mM 13C3-MG in WT and GLO2 KO cells. Data from two pulse cell experiments shown fitted with a line.
Extended Data Fig. 7 Abundance of L- and D-Lac-AAs in cells and human plasma.
(a) Basal levels of MG/LGSH and L-lactate derived metabolites in different human cell lines. The lactoylated metabolites were quantified in lysates generated from the same number of cells from each cell line, data are presented as mean values +/− SD from 5 cell cultures (n = 5). (b and c) LC-MS/MS measurements and chromatograms from three different MRM transitions of D-Lac-Phe (b) and L-Lac-Phe (c) authentic standards (top left) and their basal levels in four human plasma samples. See also Supplementary Fig. 7.
Extended Data Fig. 8
Cysteine amides react with MG and LGSH to generate Lac-Cys or lactate in GLO1 and 2 like reactions.
Supplementary information
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Daniel Opfermann, M., Bøgelund Søndergård, M., Vase Bech, L. et al. Reactivity-based metabolomics reveal cysteine has glyoxalase 1-like and glyoxalase 2-like activities. Nat Chem Biol (2025). https://doi.org/10.1038/s41589-025-01909-0
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DOI: https://doi.org/10.1038/s41589-025-01909-0
